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Peer-reviewedCC BY-NCScience Advances

SMCHD1 is a target for gene activation therapy to treat Prader-Willi syndrome

  • Megan Iminitoff1,2
  • Anna Le Fevre1,2
  • Tamara Cameron1,2
  • Hannah K. Vanyai1,2
  • Caleb Chew1,2
  • Sarah A. Kinkel1,2
  • Kelsey Breslin1,2
  • Susanne Theiß3
  • Quentin Gouil1,2
  • Merlin Thomas4
  • James M. Murphy1,2,5
  • Christian P. Schaaf3
2 more authors
  • Andrew Keniry1,2
  • Marnie E. Blewitt1,2
5 affiliations
  1. 1The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia.
  2. 2Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia.
  3. 3Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
  4. 4Department of Diabetes, Monash University, Clayton, VIC, Australia.
  5. 5Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.
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Abstract

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of expression from the active paternal allele at an imprinted cluster on chromosome 15. Current treatments address individual symptoms rather than the underlying cause of disease. Because all patients preserve a normal but epigenetically silenced maternal copy of these genes, activation of this copy offers a potential disease-modifying therapy. Here, we investigated the epigenetic regulator SMCHD1. First, we demonstrated that SMCHD1 represses the PWS locus in both mice and humans, supporting its relevance as a therapeutic target. Second, we found that SMCHD1 represses the entire PWS locus in neural lineages, extending its previously known role beyond only part of the cluster. Deleting Smchd1 after early development in vivo activated PWS genes in disease-relevant mouse tissues including hypothalamus and improved phenotypes in a PWS mouse model. Despite broader genome-wide binding, postearly development targeting of SMCHD1 appeared remarkably safe, supporting its potential for gene activation therapy for PWS.

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Cite

BibTeXRIS
BibTeX
@article{iminitoff2026smchd1,
  title = {{SMCHD1 is a target for gene activation therapy to treat Prader-Willi syndrome}},
  author = {Megan Iminitoff and Anna Le Fevre and Tamara Cameron and Hannah K. Vanyai and Caleb Chew and Sarah A. Kinkel and Kelsey Breslin and Susanne Theiß and Quentin Gouil and Merlin Thomas and James M. Murphy and Christian P. Schaaf and Andrew Keniry and Marnie E. Blewitt},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aej5702},
  url = {https://www.science.org/doi/10.1126/sciadv.aej5702},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - SMCHD1 is a target for gene activation therapy to treat Prader-Willi syndrome
AU  - Megan Iminitoff
AU  - Anna Le Fevre
AU  - Tamara Cameron
AU  - Hannah K. Vanyai
AU  - Caleb Chew
AU  - Sarah A. Kinkel
AU  - Kelsey Breslin
AU  - Susanne Theiß
AU  - Quentin Gouil
AU  - Merlin Thomas
AU  - James M. Murphy
AU  - Christian P. Schaaf
AU  - Andrew Keniry
AU  - Marnie E. Blewitt
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aej5702
UR  - https://www.science.org/doi/10.1126/sciadv.aej5702
AB  - Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of expression from the active paternal allele at an imprinted cluster on chromosome 15. Current treatments address individual symptoms rather than the underlying cause of disease. Because all patients preserve a normal but epigenetically silenced maternal copy of these genes, activation of this copy offers a potential disease-modifying therapy. Here, we investigated the epigenetic regulator SMCHD1. First, we demonstrated that SMCHD1 represses the PWS locus in both mice and humans, supporting its relevance as a therapeutic target. Second, we found that SMCHD1 represses the entire PWS locus in neural lineages, extending its previously known role beyond only part of the cluster. Deleting Smchd1 after early development in vivo activated PWS genes in disease-relevant mouse tissues including hypothalamus and improved phenotypes in a PWS mouse model. Despite broader genome-wide binding, postearly development targeting of SMCHD1 appeared remarkably safe, supporting its potential for gene activation therapy for PWS.
SN  - 2375-2548
ER  -